25% of cancer patients are diagnosed with brain metastases during the course of the disease, with the lung (50%) or breast (20%) as the most frequent site of the primary (1-3). Patients not amenable to local aggressive therapy are offered whole-brain radiotherapy (WBRT), still the mainstay of palliative treatment. Median survival after diagnosis is only 3 to 4 months, and cerebral progression is the course of death in approximately 40% of cases (4-6).
Chemotherapy is often also an option, and among the topoisomerase-II targeted drugs the most widely investigated drugs are e.g. etoposide, teniposide and doxorubicin. These drugs “poison” the nuclear enzyme topoisomerase-II. Topoisomerase-II cleaves and re-ligates double-stranded DNA, allowing the passage of another DNA strand during DNA metabolism (7). Etoposide stabilize the DNA-topoisomerase-II complex in an “open-clamp” conformation and inhibits re-sealing, thus leading to DNA damage, strand breaks and cell death (8).
Besides cytotoxicity via topoisomerase-II, etoposide in combination with radiotherapy also results in synergistic cell-kill in vitro (9-13). Synergy is obtained when drug incubation is simultaneous and post-irradiation, and when critical level of fractional cell-kill is reached, indicating an importance of the doses used. The mechanism behind this interaction is not well known; speculations about interference with DNA damage repair and the fixation of radiation induced damage has not been clarified yet.
The epipodophyllotoxins etoposide and teniposide have been tested in combination with radiotherapy in patients with both primary and metastatic brain tumour, and in SCLC with brain metastases, the response rate was 57% after concurrent WBRT and teniposide compared to 33% after teniposide alone, without increased toxicity though there was no observed increase in survival (14).
Dexrazoxane (ICRF-187) also targets topoisomerase-II, but in contrast to the poisons it catalytically inhibits the enzyme and stabilises a “closed-clamp” conformation of the DNA-topoisomerase-II complex, rendering the enzyme less sensitive to DNA-damage from poisons (15;16).
In vitro, dexrazoxane inhibits the formation of DNA strand breaks induced by topoisomerase-II poisons, and also antagonises toxicity from etoposide in clonogenic assay (17).
WO97/24044 discloses topoisomerase-II poisons in combination with bis-dioxypiperazine derivatives as a combined therapy for the treatment of tumours.